A community randomized controlled trial of insecticide-treated bednets for the prevention of malaria and anaemia among primigravid women on the Kenyan coast

Summary The effectiveness of insecticide-treated bednets (ITBN) in preventing malaria and anaemia among primigravidae living in Kilifi District, Kenya, was assessed by a randomized controlled trial between September 1994 and November 1995. All residents within 28 community clusters received ITBN in July 1993, whilst residents of another 28 clusters served as contemporaneous controls. All resident primigravid women with singleton pregnancies attending antenatal care at Kilifi District Hospital were eligible for recruitment. 503 primigravidae were recruited. 91.4% were anaemic antenatally (Hb < 11 g/dl): 91.0% from the intervention arm and 92.0% from the control arm. Severe anaemia (Hb < 7 g/dl) was found among 15.1% of intervention women and 20.1% of control women ( P = 0.28). No significant differences were observed in reports of febrile illness or the presence of chloroquine in the serum or peripheral parasitaemia during the third trimester between the two groups. In the women delivering in hospital ( n = 130), there was no association between placental malaria infection and the intervention: 77.4% of placentas from control women had evidence of past or active infection, compared with 72.0% of placentas from intervention women ( P = 0.76). Similarly, in the women delivering in hospital, ITBN did not improve birth weight, and there were no differences in perinatal mortality between the two study groups. Despite ITBN having a great impact on paediatric severe malaria and mortality in this transmission setting, there was very little impact of ITBN on the morbidity associated with malaria infection in primigravidae. Alternative strategies are required to tackle this continued public health problem for pregnant women living in endemic areas similar to the Kenyan Coast.     

Insecticide-treated bednets reduce mortality and severe morbidity from malaria among children on the Kenyan coast

New tools to prevent malaria morbidity and mortality are needed to improve child survival in sub-Saharan Africa. Insecticide treated bednets (ITBN) have been shown, in one setting (The Gambia, West Africa), to reduce childhood mortality. To assess the impact of ITBN on child survival under different epidemiological and cultural conditions we conducted a community randomized, controlled trial of permethrin treated bednets (0.5 g/m²) among a rural population on the Kenyan Coast. Between 1991 and 1993 continuous community-based demographic surveillance linked to hospital-based in-patient surveillance identified all mortality and severe malaria morbidity events during a 2-year period among a population of over 11 000 children under 5 years of age. In July 1993, 28 randomly selected communities were issued ITBN, instructed in their use and the nets re-impregnated every 6 months. The remaining 28 communities served as contemporaneous controls for the following 2 years, during which continuous demographic and hospital surveillance was maintained until the end of July 1995. The introduction of ITBN led to significant reductions in childhood mortality (PE 33%, CI 7–51%) and severe, life-threatening malaria among children aged 1–59 months (PE 44%, CI 19–62). These findings confirm the value of ITBN in improving child survival and provide the first evidence of their specific role in reducing severe morbidity from malaria.     

The effect of malaria on mortality in a cohort of HIV-infected Ugandan adults

OBJECTIVES: To investigate the effects of malaria parasitaemia and clinical malaria on mortality in HIV seropositive and seronegative adults. METHODS: A cohort of adults in rural Uganda were followed from 1990 to 1998. Participants attended routine clinic visits every 3 months and also when sick (interim visits). Information was collected on HIV serostatus, history of fever, current fever and malaria parasite levels. Malaria was categorized as any parasitaemia, significant parasitaemia (>/=1.25 x 10(6) parasites/ml at routine or >/=50 parasites per 200 white blood cells at interim visits) or clinical malaria. The effect of malaria on all-cause mortality was assessed using Cox models. RESULTS: The 222 HIV seropositive participants made 2762 routine visits and 1522 interim visits. During follow-up, of the 211 participants with full records, 69% had at least one episode of parasitaemia, 51% experienced significant parasitaemia and 28% had clinical malaria. There were 90 deaths in 922 person-years of observation. There were no significant associations between numbers of visits with any parasitaemia, significant parasitaemia or clinical malaria on mortality rates. The highest mortality rates were observed in those making four or more routine visits with significant parasitaemia [adjusted mortality rate ratio (RR) 3.27 compared with those making 0 such visits; P=0.078] and those making two or more visits with clinical malaria (adjusted RR 2.23; P=0.093). There was no significant interaction between any malaria category and HIV serostatus. Conclusion We found no evidence of a strong detrimental effect of malaria on all-cause mortality in HIV seropositive adults in this setting.     

Prevention of lymphatic filariasis with insecticide-treated bednets in Cambodia

Potential risk factors for lymphatic filariasis (LF), including the failure to use insecticide-treated bednets (ITN), were studied in four north-eastern provinces of Cambodia, using 43 cases of LF and 248 apparently healthy controls who were matched with the cases in terms of age (+/-5 years), gender and village. The results of a univariate matched analysis indicated that lack of ITN [odds ratio (OR)=20.1; 95% confidence interval (CI)=2.2-182.4; P=0.008] and frequent overnight stays in forests or paddy fields outside the village (OR=3.6; CI=1.3-10.0; P=0.012) were the most important risk factors. In a multivariate matched analysis, frequent overnight stays outside the village combined with bednet use showed a clear dose-response relationship, with untreated nets offering significant protection during such stays but ITN offering significantly better protection. Even if villagers used ITN during such stays, they were significantly more likely to develop LF than villagers who did not travel (OR=5.0; CI=1.5-16.3; P=0.008), and if they used untreated or no nets while away they were even more likely than the non-travellers to develop the disease (OR=1413; CI=28.0-71,189; P<0.001). Taken together, these results provide further evidence for the importance of bednet use and their impregnation in the prevention of LF. At least in north-eastern Cambodia, the use of bednets and, preferably, ITN is particularly important during overnight stays outside the home village. In areas where LF is endemic, the sustained distribution of insecticide-treated bednets or hammock nets appears to be a very good idea.     

The impact of insecticide-treated bednets on malaria and anaemia in pregnancy in Kassena-Nankana district, Ghana: a randomized controlled trial

The impact of insecticide-treated bednet use on malaria and anaemia in pregnancy was assessed, as a supplementary study, in a major WHO/TDR-supported bednet trial in northern Ghana between July 1994 and April 1995. The study area was divided into 96 clusters of compounds, with 48 clusters being randomly allocated to intervention. All pregnant women were included in the study but the focus was on primigravidae and secundigravidae. 1961 pregnant women were recruited into the study--1033 (52.7%) in the treated bednet group and 928 (47.3%) in the no net group. 1806 (92.1%) had blood taken for malaria microscopy and haemoglobin determination in the third trimester. Pregnancy outcomes were reported for 847 women. The characteristics of women in intervention and control groups were comparable. The odds ratios, with 95% confidence interval (CI), for different study endpoints were, for Plasmodium falciparum parasitaemia--0.89 (0.73, 1.08), for anaemia--0.88 (0.70, 1.09), for low birthweight (LBW)--0.87 (0.63, 1.19), indicating no benefit for treated bednet use. Effective net use by parity varied from 42% in primigravidae to 63% in multigravidae, in spite of free nets and insecticide impregnation. The main reasons for not using a net were warm weather and perceived absence of mosquito biting. Chloroquine use in pregnancy was low and comparable in both groups. Implications of findings for malaria control in pregnancy and further research are discussed.     

Host polymorphisms and the incidence of malaria in Ugandan children

Mutations in beta-globin, glucose-6-phosphate dehydrogenase, and promoters for tumor necrosis factor-alpha and inducible nitric oxide synthase (iNOS) were examined for associations with the incidence of symptomatic malaria in a cohort of 307 Ugandan children. After adjustment of incidence rates for age, water source, use of preventative measures, and proximity to mosquito breeding sites, glucose-6-phosphate dehydrogenase A- heterozygous females had a significantly higher incidence of malaria (incidence rate ratio [IRR] = 1.63, P = 0.03) and a trend towards higher parasite densities (37,100 versus 26,200 parasites/microL; P = 0.18) compared with wild-type children. Male hemizygotes had trends in the same direction. Heterozygotes for sickle hemoglobin had trends toward a lower incidence of malaria and lower parasite density at presentation. Heterozygotes for the iNOS promoter G954C polymorphism, but not other promoter polymorphisms, had a significantly lower incidence of malaria compared with wild-type children (IRR = 0.69, P = 0.05). Host polymorphisms appear to impact upon the incidence of uncomplicated malaria in Ugandan children.     

Effects of maternal vitamin supplements on malaria in children born to HIV-infected women

Vitamin deficiencies are frequent in children suffering from malaria. The effects of maternal multivitamin supplementation on the risk of malaria in children are unknown. We examined the impact of providing multivitamins or vitamin A/beta-carotene supplements during pregnancy and lactation to HIV-infected women on their children's risk of malaria up to 2 years of age, in a randomized, placebo-controlled trial. Tanzanian women (N = 829) received one of four daily oral regimens during pregnancy and after delivery: 1) vitamins B, C, and E (multivitamins); 2) vitamin A and beta-carotene (VA/BC); 3) multivitamins including VA/BC; or 4) placebo. After 6 months of age, all children received 6-monthly oral vitamin A supplements irrespective of treatment arm. The incidence of childhood malaria was assessed through three-monthly blood smears and at monthly and interim clinic visits from birth to 24 months of age. Compared with placebo, multivitamins excluding VA/BC reduced the incidence of clinical malaria by 71% (95% CI = 11-91%; P = 0.02), whereas VA/BC alone resulted in a nonsignificant 63% reduction (95% CI = -4% to 87%; P = 0.06). Multivitamins including VA/BC significantly reduced the incidence of high parasitemia by 43% (95% CI = 2-67%; P = 0.04). The effects did not vary according to the children's HIV status. Supplementation of pregnant and lactating HIV-infected women with vitamins B, C, and E might be a useful, inexpensive intervention to decrease the burden of malaria in children born to HIV-infected women in sub-Saharan Africa.     

Sustained high coverage of insecticide-treated bednets through combined Catch-up and Keep-up strategies

BACKGROUND: Mass, free distribution (Catch-up) of insecticide-treated bednets (ITNs) during measles vaccination campaigns achieves immediate, high and equitable coverage for both ITNs and measles vaccine. Maintaining high coverage over time requires long-term, routine access to new nets (Keep-up). In many settings, only one approach--either campaign or routine delivery--has been available and have been seen as competing methods. Relying only on campaigns achieves high coverage at the cost of lack of later access. Relying solely on routine coverage builds a delivery infrastructure but may lead to slower rates of coverage and inequities. A combined Catch-up/Keep-up approach has been a common feature of vaccination programs for many years. We assessed the 3-year effects of a one-time Catch-up campaign followed by clinic-based social marketing for routine Keep-up on ITN coverage and use. METHODS: In December 2002, ITNs were distributed to all children attending a measles vaccination campaign in a rural district of Ghana. In the 3 years following that campaign, the district began offering ITNs at a subsidized price to pregnant women attending ante-natal clinics. This Keep-up scheme did not become fully operational until 2 years after the campaign. A coverage survey was conducted 38-month post-campaign using a standard two-stage cluster sampling method. RESULTS: Coverage of nets was high due to the combined contributions of both Catch-up and Keep-up. There were 475 households in the survey with at least one child less than 5 years of age. Among these households, coverage was 95.6% with any net, 83.8% with a campaign net, and 73.9% with an ITN. Of all children, 95.7% slept in a household that had a net, 86.1% slept in a household that had a campaign net. Not all available nets were used as only 59.6% of children slept under an ITN. The source of the nets was 77.7% from the campaign and 20% from routine clinics. Compared to households that participated in the campaign, households with children born after the campaign had higher rates of net ownership (75.1% vs. 67.7%, P=0.04). Equity was high as the ratio of coverage in the lowest wealth quintile to that in the highest was 0.95 for ITN ownership and 1.08 for ITN use. These coverage and use rates were similar to those previously reported 5-month post-campaign, suggesting no decrease over 3 years. CONCLUSION: A high level of ITN coverage and use was achieved and sustained by sequential community-based mass campaign Catch-up and clinic-based Keep-up distribution. The campaign nets covered virtually all extant households while clinic-based distribution provided nets for the new sleeping spaces created post-campaign. Because nets can be shared, and most children are born into families that already have a net, the number of new nets needed to sustain high coverage is substantially lower than the number of newborn children. A Catch-up/Keep-up strategy combining mass campaigns for children and clinic-based distribution to pregnant women is an efficient strategy for achieving and sustaining high net coverage. Assuring proper use of nets is a remaining challenge.     

Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease

BACKGROUND: Trimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for persons living with human immunodeficiency virus infection and acquired immunodeficiency syndrome in Africa. TS and the antimalarial combination sulfadoxine-pyrimethamine (SP) share mechanisms of action and resistance patterns, and concerns about the impact of TS resistance on SP efficacy have contributed to reluctance to implement TS prophylaxis in Africa. METHODS: To determine whether TS prophylaxis impairs SP efficacy for treatment of uncomplicated falciparum malaria, we conducted a randomized, controlled, open-label study of TS prophylaxis. Two hundred and forty children 5-15 years old were randomized in a 2 : 1 fashion to receive either thrice-weekly TS for 12 weeks or no prophylaxis and were treated with SP for subsequent episodes of malaria. The incidence of malaria, SP efficacy, and the prevalence of parasite mutations that confer antifolate drug resistance were measured. RESULTS. TS prophylaxis had a 99.5% protective efficacy against episodes of clinical malaria, with 97% efficacy against infection. Four SP treatment failures occurred in the control group, and none occurred in the TS group. No evidence was seen for selection by TS of antifolate resistance-conferring mutations in parasite dihydrofolate reductase or dihydropteroate synthase during subclinical infections. CONCLUSIONS. In this setting of low antifolate resistance, TS was highly effective in preventing falciparum malaria infection and disease and did not appear to select for SP-resistant parasites.     

Comparison of the cost and cost-effectiveness of insecticide-treated bednets and residual house-spraying in KwaZulu-Natal, South Africa

Residual house-spraying (RHS) has been the mainstay of South African malaria prevention for more than 50 years, but it has been argued that insecticide-treated bednets (ITBN) could be a more effective and appropriate method of control. To provide a rational basis for choosing between the interventions, a trial was conducted during 1998 and 1999 in northern KwaZulu-Natal to collect comparable data on the effectiveness, acceptability and cost of the two interventions. The current practice of house-spraying once a year was compared with ITBN, distributed free to households and retreated annually at several specific centres. The base case results show ITBN to be significantly more effective in preventing malaria cases than RHS (overall adjusted rate ratio of 0.69), and also more costly, with an incremental economic cost per person of ITBN compared with RHS of R8.68 (US$1.42) per year, giving a gross incremental cost per case averted of R111 ($18) (1999 prices). Estimating the number of deaths averted, based on the average case fatality rate, gave a gross incremental cost per death averted of R11 718 ($1915). The additional cases averted were estimated to lead to drug cost savings of around R1 ($0.16) per capita per year, giving a net cost per case averted of R98 ($16), and net cost per death averted of R10 377 ($1696). Although the finding that the economic costs of ITBN were higher than those for RHS was relatively robust to parameter variations, the extent of the cost margin was sensitive to changes in the price and useful life of the net, and the price of the insecticide. Moreover, a switch to ITBN could lead to net financial savings if the price per net fell below $3.57 (R21.85), or if a change in policy allowed a significant reduction in the number of permanent full-time malaria control staff. In view of the greater effectiveness of ITBN, policy makers may view ITBN as a cost-effective use of resources, even if the economic costs are higher. If ITBN are implemented, close monitoring will be required of use, retreatment and useful life of nets, and resistance to insecticides, to assess any change over time in relative cost-effectiveness, and any threat to the role of the programme as a barrier to the spread of malaria transmission to other areas.     

Pigmented monocytes are negative correlates of protection against severe and complicated malaria in Ugandan children

Pigmented leukocytes are reported to be associated with severe malaria (SM). Blood smears from a case-control study of SM conducted in Apac Hospital in Northern Uganda were examined for pigmented leukocytes to investigate their association with measures of disease and clinical immunity in children less than 5 years old. Pigmented leukocytes, predominated by monocytes, were significantly greater in number in SM by comparison with uncomplicated malaria (UM). SM children with no pigmented leukocytes had significantly elevated hemoglobin, packed cell volumes, and titers of IgG anti-SERA5 by comparison with SM children with pigmented leukocytes. These differences were not observed in UM. A Spearman rank correlation analysis showed, in addition, a negative but weak correlation between pigmented monocytes and titers of IgG anti-Plasmodium falciparum lysate and IgG anti-EBA-175 in both SM and UM children. Thus, numbers of pigmented monocytes might be negative correlates of clinical immunity in a region of holoendemic malaria.     

Maintenance and sustained use of insecticide-treated bednets and curtains three years after a controlled trial in western Kenya

In large experimental trials throughout Africa, insecticide-treated bednets and curtains have reduced child mortality in malaria-endemic communities by 15%-30%. While few questions remain about the efficacy of this intervention, operational issues around how to implement and sustain insecticide-treated materials (ITM) projects need attention. We revisited the site of a small-scale ITM intervention trial, 3 years after the project ended, to assess how local attitudes and practices had changed. Qualitative and quantitative methods, including 16 focus group discussions and a household survey (n = 60), were employed to assess use, maintenance, retreatment and perceptions of ITM and the insecticide in former study communities. Families that had been issued bednets were more likely to have kept and maintained them and valued bednets more highly than those who had been issued curtains. While most households retained their original bednets, none had treated them with insecticide since the intervention trial was completed 3 years earlier. Most of those who had been issued bednets repaired them, but none acquired new or replacement nets. In contrast, households that had been issued insecticide-treated curtains often removed them. Three (15%) of the households issued curtains had purchased one or more bednets since the study ended. In households where bednets had been issued, children 10 years of age and younger were a third as likely to sleep under a net as were adults (relative risk (RR) = 0. 32; 95% confidence interval (95%CI) = 0.19, 0.53). Understanding how and why optimal ITM use declined following this small-scale intervention trial can suggest measures that may improve the sustainability of current and future ITM efforts.     

Successful prophylaxis against Pneumocystis carinii pneumonia in HIV-infected children using smaller than recommended dosages of trimethoprim-sulfamethoxazole

Prophylaxis against Pneumocystis carinii pneumonia (PCP) is an essential part of the management of children with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). No dose-ranging studies were ever performed; therefore, the amount of trimethoprim-sulfamethoxazole (TMP-SMX) needed to suppress PCP in children with HIV/AIDS is not known. The dose recommended by the Centers for Disease Control (CDC) has been thought to be just above the threshold needed for prevention, based on anecdotal breakthrough PCP in cancer patients who were improperly dosed. We have been giving prophylaxis based on body weight rather than surface area, and this, combined with growth of our children, has led to a large experience with dosages lower than the currently recommended 150 mg/m2. The medical records of children with HIV who met CDC guidelines for institution of PCP prophylaxis were reviewed. To ascertain the per square meter (m2) dosage each child was receiving, body surface area was calculated from height and weight measurements. Dosages were recalculated every 6 months and at each dosage change. Data regarding PCP infection, bacterial infections, and side effects of TMP-SMX were extracted. Data were compiled from 1,719.5 child-months of TMP-SMX prophylaxis, including 1,532.5 child-months below the currently recommended dose. Sixty-seven percent of our child-months were at or below two-thirds the CDC recommended dose. There were no cases of proven or suspected PCP. Incidence of other serious bacterial infections was low. Bacteremia and sepsis with Streptococcus pneumoniae was the most common proven bacterial infection, at a rate of 5.5 episodes per 100 child-years. The incidence of bacterial infection did not vary by the dose of TMP-SMX. TMP-SMX prophylaxis was well tolerated; most reactions were mild and self-limited and did not recur with re-institution of the drug. Only 6.1% of this cohort had TMP-SMX prophylaxis discontinued due to perceived toxicity. These data show that the currently recommended dose of TMP-SMX (150 mg/m2) may not be required to prevent PCP in children with HIV/AIDS. The drug is well tolerated at all dosage levels. The incidence of serious bacterial infection in this cohort of patients did not depend upon the amount of TMP-SMX prescribed. A prospective, controlled clinical trial of low-dose TMP-SMX for children with HIV infection is warranted.     

Urban malaria: primary caregivers' knowledge,attitudes, practices and predictors of malaria incidence in a cohort of Ugandan children

OBJECTIVES: To assess malaria-related knowledge, attitude and practices (KAP) among primary caregivers, to identify associations between primary caregivers' characteristics and positive KAP towards malaria, and to identify independent predictors of childhood malaria incidence in an urban setting. METHODS: Children aged 6 months to 5 years living in Kampala, Uganda were enrolled as part of a longitudinal study on antimalarial therapy. Primary caregivers of 307 children were interviewed and information was collected on demographics, malaria-related KAP, environmental and household factors. Malaria incidence was measured prospectively using passive surveillance. RESULTS: A total of 90% of respondents reported mosquitoes and/or malaria as the cause of fever. Caregivers reported that if their child had fever, 63% would go to a clinic or hospital as their first action and 97% as their first or second action. Only 38% knew that chloroquine was the recommended first-line treatment for malaria and 29% knew the correct dose. Preventive measures for malaria were reported in 45% of households but only 25% reported using bednets. Higher levels of education for the caregiver were associated with positive malaria-related KAP. Malaria incidence varied widely. The following were independent predictors of malaria incidence: (1). Children aged 24-41 months at enrolment had a higher incidence of malaria. (2). Reported bednet or chemoprophylaxis use reduced the incidence of malaria. (3). A child's place of residence was associated with incidence. (4). Children from households using open water sources had a higher incidence than those using closed sources. CONCLUSION: Primary caregivers were knowledgeable about malaria and used modern health care facilities but knew less about the proper administration of antimalarials and had limited use of preventive measures. Malaria incidence was associated with child's age at enrolment, geography, source of water and the use of preventive measures.     

Spatial effects of the social marketing of insecticide-treated nets on malaria morbidity

Randomized controlled trials have shown that insecticide-treated nets (ITNs) have an impact on both malaria morbidity and mortality. Uniformly high coverage of ITNs characterized these trials and this resulted in some protection of nearby non-users of ITNs. We have now assessed the coverage, distribution pattern and resultant spatial effects in one village in Tanzania where ITNs were distributed in a social marketing programme. The prevalence of parasitaemia, mild anaemia (Hb <11 g/dl) and moderate/severe anaemia (Hb <8 g/dl) in children under five was assessed cross-sectionally. Data on ownership of ITNs were collected and inhabitants' houses were mapped. One year after the start of the social marketing programme, 52% of the children were using a net which had been treated at least once. The ITNs were rather homogeneously distributed throughout the village at an average density of about 118 ITNs per thousand population. There was no evidence of a pattern in the distribution of parasitaemia and anaemia cases, but children living in areas of moderately high ITN coverage were about half as likely to have moderate/severe anaemia (OR 0.5, 95% CI: 0.2, 0.9) and had lower prevalence of splenomegaly, irrespective of their net use. No protective effects of coverage were found for prevalence of mild anaemia nor for parasitaemia. The use of untreated nets had neither coverage nor short distance effects. More efforts should be made to ensure high coverage in ITNs programmes to achieve maximum benefit.